The hypothalamus-pituitary-adrenal axis in fetal sheep plays an important role in fetal maturation, in the timing of parturition and in homeostatic responses to stress. Elucidation of the physiological mechanisms controlling this axis and its influence on other endocrine axes will improve understanding of essential processes that direct the transition from fetal to adult life. Previous experiments have demonstrated that cortisol inhibits fetal ACTH and renin activity responses to hypotension. The present experiments will investigate developmental aspects of the physiological role of cortisol in the control of ACTH and renin secretion in sheep. Specifically, these experiments will: quantitate the sensitivity of the ovine fetal hypothalamo-pituitary unit to physiological increases in plasma cortisol concentration and compare this sensitivity to that of the adult; quantitate dose-response relationships between physiological increases in fetal plasma cortisol and the degree of inhibition of fetal renin responses to hypotension and compare the sensitivity of this interaction to that in adult sheep; account for plasma binding of cortisol as a modulator of cortisol efficacy; determine the timecourses of interaction between cortisol, ACTH and renin in fetal and adult sheep; test the effect of cortisol on renin substrate production and renin secretion in both fetal and adult sheep; elucidate the role of maternal corticosteroids in the control of fetal ACTH and renin secretion; quantitate the rate of transfer of cortisol from mother to fetus and test the effect of increased maternal plasma cortisol concentration on this rate of transfer. The experiments proposed in this grant application will prove or disprove the physiological significance of the effects of cortisol on ACTH and renin secretion in fetal sheep and will test for the developmental changes in these interactions. Results will provide a firm theoretical basis for future experiments investigating the role of fetal and maternal cortisol stress responses in the control of ACTH, renin-angiotensin and possibly cardiovascular, responses to subsequent or concomitant stress. Results will also provide a theoretical basis for better understanding of the homeostatic and/or developmental consequences of maternal or fetal stress or of maternal glucocorticoid therapy.